The exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, specially in the prefrontal cortex (PFC) and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fluorescent excitatory and inhibitory neurons, received a single injection of MK801 (NMDAR antagonist) or vehicle solution at postnatal day 7 and/or were socially isolated from the age of weaning until adulthood (3 months old). We found that anxiety-related behavior, brain volume, neuronal structure and the expression of molecules related to plasticity and E/I neurotransmission in adult mice were importantly affected by early-life stress. Interestingly, many of these effects were potentiated when the stress paradigm was applied to mice perinatally injected with MK801 ("double-hit" model). These results clearly show the impact of early-life stress on the adult brain, specially on the structure and plasticity of inhibitory networks and highlight the double-hit model as a valuable tool to study the contribution of early-life stress in the emergence of neurodevelopmental psychiatric disorders, such as schizophrenia.
Significance Statement The double-hit model constitutes a valuable tool for future experiments exploring the effects of aversive experiences during early life and the biological basis of mental disorders such as schizophrenia. It also supports the emerging hypothesis of altered E/I balance in key brain regions as one of the underlying causes of the disease. Our study also supports the idea that such imbalances may arise from problems in initial neural circuit formation or its maintenance, because we found alterations in the structure of inhibitory circuits and also in the expression of molecules related to their plasticity and maturation.
All authors reported no biomedical financial interests or potential conflicts of interest.
Authors' contributions: EC-G & JN designed the study. EC-G, MP-R, MB, JG-J, JVL, HC, CB-F, CG-M, BR-M, YC & NS-O performed the experiments. EC-G & MP-R analyzed the data. EC-G & MP-R prepared the figures. EC-G, MP-R & JN wrote the manuscript. MDM supervised the molecular part of the project. JN supervised the whole project. All authors read and approved the final manuscript.
This work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2012-32512, SAF2015-68436-R), Generalitat Valenciana (PROMETEO2013/069) and Fundación Alicia Koplowitz (FAK2012-01). MP-R and YC hold pre-doctoral fellowships from the Spanish Ministry of Education (FPU12/03200, FPU13/04764) and MB, from the University of Valencia (‘Atracció de talent-VLC campus’).